General pathology
Lecture -3Dr. Ali Zeki
Mechanisms of cellular injury:
The four cell systems particularly affected during cell injury are:
1- Cell membrane integrity critical to cellular ionic and osmotic
homeostasis.
2- ATP (Adenosine Tri-Phosphate), generation by mitochondrial
aerobic respiration.
3- Protein synthesis.
4- Integrity of genetic apparatus.
Hypoxic/Ischemic Injury:
1-First consequence is loss of oxidative phosphorylation and reduction in
ATP production.
Reduction of ATP lead to the following:
 Failure of ATP dependent Na/K ATPase enzyme that responsible for
pumps Na outside the cell , and maintains high cell K and low cell Na and
Ca. So now K decreases and Na and Ca increase within the cell. When Na
level increase within the cell this well trap a lot of water and this lead to cell
swelling. Increase Ca influx lead to many effects like activation of
phospholipase enzyme that disrupt the cell membrane.
 Decrease in ATP lead to increases glycolysis, the process of glycogen
degradation leads to production of lactic acid and decrease pH within the
cell and decrease glycogen stores
2- Decrease protein synthesis, due to loss of ATP needed for synthesis of
proteins and detaching of ribosomes from RER due to ER swells. Reduction
of protein synthesis well lead to membrane disruption, decreased
mitochondrial function, and disruption of the cytoskeleton.
3-Cell membrane defect:
Membrane function depends mostly on
mitochondrial function, phospholipid loss of membrane components, mostly
from endogenous phospholipase activation, and decreased synthesis of new
phospholipids. Cytoskeleton attaches to plasma membrane and strengthens
it. Proteases may damage this connection and the plasma membrane is thus
more susceptible to rupture.
4- Lysosomal membrane injury causes release of enzyme contents that
eventually lead to irreversible nuclear damage.
Reperfusion injury:
Much of the damage from ischemia or hypoxia occurs on the reestablishment of circulation: reperfusion can help restore health to
reversibly damaged cells, but can also lead to cell death.
Mechanisms of reperfusion injury:
1-Circulation brings PMNs (neutrophils especially) that release toxic oxygen
radicals that do damage to membranes. Damaged cells may express
cytokines that attract PMNs to them and cause inflammation with additional
injury.
2- Reperfusion brings a massive influx of Ca++ which leads to activation of
phospholipases, endonucleases, proteases (cytoskeleton), and DNAases
3- Formation of oxygen free radicals, (O•, H2O2, and •OH).
Oxygen radicals (free unpaired electron in outer orbit) do three main
things:
1.Lipid peroxidation takes an unsaturated fatty acid in membrane
phospholipids and crease a damaged lipid and peroxide, which is
autocatalytic and does more damage
2.Promotes sulfhydryl mediated protein cross linking that creates disulfide
bonds which inactivate enzymes
3.Interact with DNA causing mutations.
Apoptosis:
differs significantly from necrosis. It is an energy dependent
physiological process involved in removing unwanted individual cells
and is a specialized form of programmed cell death that is characterized
by:
o chromatin condensation and formation of cytoplasmic membrane blebs
(cell surface deformities caused by a cytoskeleton disruption)
o breakdown of DNA into nucleosome-sized fragments
o a minimal inflammatory response
It has a central role in morphogenesis, maintaining organ size, and
atrophy.
Apoptosis can also occur in the removal of defective cells.
Mechanisms :
Apoptosis begins with the activation of endogenous proteases and
endonucleases , this results in the degradation of the cytoskeletal
structure, fragmentation of DNA and loss of mitochondrial function.
The cell shrinks, retaining its plasma membrane, however, if the plasma
membrane is altered, phagocytosis occurs. Cells not phagocytosed break
into smaller membrane-bound fragments called apoptotic bodies. These is
no inflammatory reaction to these bodies.
Apoptosis vs. Necrosis : comparison
Features
Necrosis
Causes
Invariably due to
pathological injury
Affects
Mechanisms
Cell groups
Impairment or
cessation
of ion homeostasis
Lysosomes leak lytic
enzymes
Cell swelling and lysis
Morphology
Fate
Common
Phagocytosed by
neutrophil polymorphs
and macrophages
Apoptosis
May be induced by
physiological or
pathological stimuli
Single cells
Energy-dependent
fragmentation of DNA
by endogenous
endonucleases
Lysosomes intact
Cell shrinkage and
fragmentation to form
apoptotic bodies with
dense chromatin
None
Phagocytosed by
neighboring cells
programmed cell death can occurs normally in many conditions like:
1- Aging.
2-Development (Embryogenesis).
3-Defense mechanism in the immune system. Specific examples include T
cell deletions in thymus.
4-Embyrogenesis (loss of tissue between fingers),
5-Hormone dependent involution (return of uterine lining to normal
following pregnancy).
6-Cell death in tumors.
7-Neutrophilic death in acute inflammation.
Morphological changes:
cells are smaller with dense cytoplasm. The chromatin is condensed in
fragments near the nuclear periphery. Apoptotic bodies form, which are
membrane bound with some cytoplasm and organelles and sometimes
nuclear fragments. These are taken up by normal cells nearby and degraded
in lysosomes.
Unregulated apoptosis plays a role in a variety of diseases.
A- When inhibited, cells may survive longer as in cancer and autoimmune
disorders.
B- When accelerated, cells may die sooner as in AIDS depletion of
lymphocytes and degenerative neurological disorders.